title: Des-acyl ghrelin fragments evoke endothelium-dependent vasodilatation of rat mesenteric vascular bed via activation of potassium channels.
abstract: The mechanisms that subserve ghrelin-evoked vasodilatation have not been elucidated in previous studies. Changes in perfusion pressure evoked by ghrelin and its N-terminal fragments were examined ex vivo in phenylephrine-constricted perfused mesenteric vascular beds of male Sprague Dawley rats maintained at a constant flow rate. Both ghrelin (maximum effect [E(max)] 45%) and des-acyl ghrelin (E(max) 43%) evoked vasodilatation at concentrations between 10 pM and 1 nM, compared to acetylcholine (median effective concentration [EC(50)] 3 nM; E(max) 93%). Those responses were abolished in endothelium-denuded preparations, and in endothelium-intact preparations exposed to either calcium-activated potassium channel, or a depolarizing stimulus, or in the presence of a combination of either apamin and 1,2-chlorophenyl diphenylmethyl-1 H-pyrazole (triarylmethane-34 [TRAM-34]), or ouabain and barium. ATP-activated potassium channel blockade, or a combination of nitric oxide synthase and cyclooxygenase inhibition had no effect. The classical growth hormone secretagogue antagonist, [d-Lys(3)]-growth hormone-releasing peptide (10 nM), or several N-terminal fragments of des-acyl ghrelin, including the tripeptide glycine-serine-serine (G-S-S [1 nM]), showed endothelium-dependent vasodilatation like des-acyl ghrelin, while responses to glycine-serine or serine-serine were relatively lower. A higher concentration (100 muM) of l-serine, but not glycine, evoked vasodilatation of similar magnitude. The serine dense N-terminal sequence of des-acyl ghrelin mediates endothelium-dependent vasodilatation via activation of apamin+TRAM-34 sensitive small- and intermediate-conductance calcium-activated potassium channels present on the mesenteric endothelium. Thus, the vasodilator response to ghrelins in the perfused rat mesenteric vascular bed is not mediated by the classical growth hormone secretagogue receptor type 1a.
authors.affiliation: Department of Pharmacology and the Cardiovascular Research Group (CVRG), College of Medicine, University of Saskatchewan, Saskatoon, SK., Canada.
authors.forename: Banafsheh
authors.initials: B
authors.lastname: Moazed
authors.forename: Dale
authors.initials: D
authors.lastname: Quest
authors.forename: Venkat
authors.initials: V
authors.lastname: Gopalakrishnan
mesh_terms: D000818:Animals; D001685:Biological Factors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D054439:Ghrelin / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D008642:Mesenteric Veins / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D010477:Perfusion; D010656:Phenylephrine / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D054440:Receptors, Ghrelin / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D001685:Biological Factors; D054439:Ghrelin; D010446:Peptide Fragments; D024681:Potassium Channels, Calcium-Activated; D054440:Receptors, Ghrelin; D014662:Vasoconstrictor Agents; C067410:endothelium-dependent hyperpolarization factor; C422650:ghrelin, des-n-octanoyl; D010656:Phenylephrine